INFLUENCE OF SELF-EMULSIFYING DRUG DELIVERY SYSTEMS ON THE AQUEOUS SOLUBILITY AND DISPERSION OF CINNARIZINE

MastersPurpose: Oral route is considered to be the most convenient and preferred route for the patient among various routes of drug delivery systems. However, oral delivery of many drug compounds is hampered because of the high lipophilicity of the drug itself. Nearly 40% of new drug candidates exhibit poor water solubility which leads to poor oral bioavailability, high intra- and inter-subject variability and lack of dose proportionality. To overcome these limitations, different techniques such as using carrier systems and complexation with cyclodextrins have been used to enhance the solubility of poorly water-soluble drugs (PWSD) but the enormous cost and complexity of manufacturing process have limited their commercial viability. However, formulating PWSD in self-emulsifying and/or self-microemulsifying drug delivery system (SEDDS/SMEDDS, respectively) offers an attractive alternate. SEDDS/SMEDDS are oral lipid dosage forms containing mixture of oil, surfactant, drug and possibly other components which can form a fine emulsion or microemulsion upon dilution in the aqueous lumen of the gut offering an improvement in the rate and extent of absorption and more reproducible plasma-concentration profiles. SEDDS/SMEDDS offer exclusive advantage over conventional formulations in the spontaneous formation with low energy requirement beside the excellent thermodynamic stability. Cinnarizine (CN), a highly lipophilic compound with log P = 5.8, was selected as a model drug for the current thesis. The key objective of the work is to design SEDDS/SMEDDS capable of presenting and maintaining the drug in solution for sufficient time to allow for absorption. Methods: Initially, an isocratic reverse phase chromatographic method employing ultra performance liquid chromatography (UPLC) was developed for the quantification of CN in pure and pharmaceutical formulations. The proposed method was successfully validated with respect to the standard FDA guidelines. Mainly, the work involved designing and characterizing SEDDS/SMEDDS formulations of CN. The designed formulations were initially screened for their selfemulsification efficiency. Equilibrium phase diagrams were constructed to evaluate phase changes that can occur at various stages of aqueous dilution. The equilibrium solubility within anhydrous and diluted formulations was investigated to determine the formulation solvent capacity and speculate their precipitation tendency, respectively. The droplet size distribution was measured upon (1:1000) aqueous dilution of SEDDS/SMEDDS formulations. Dynamic dispersion studies were carried out mainly to assess the precipitation magnitude upon aqueous dilution of the formulation. Furthermore, in-vitro dissolution studies were conducted to compare the dissolution profiles of selected SEDDS/SMEDDS formulations with the marketed Stugeron® tablets. Finally, the work involved stability assessment of CN within SEDDS/SMEDDS formulations at accelerated and long-term storage conditions. Results: SEDDS/SMEDDS formulations have shown diverse self-emulsification efficiencies depending on the oil and surfactant components. The best self-emulsification efficiencies were reported with mixed glycerides and/or hydrophilic surfactants. Equilibrium phase diagram studies revealed that a minimum of 50% surfactant was needed to achieve efficient self-emulsification. Increasing the monoglycerides concentration within the oil component led to enhancing water solubilization thus enhancing the self-emulsification efficiency. The CN solubility within the anhydrous formulations showed remarkable variability according to the formulation type and composition. The CN solubility increased with increasing the lipid chain length and/or surfactant lipophilicity. Determining the CN solubility within the diluted formulations revealed that the total mass in solution almost remained the same which suggests no precipitation tendency. The mean droplet size of the diluted formulations decreased in case of using mixed glycerides, with decreasing the lipid chain length and/or increasing surfactant hydrophilicity. In case of dynamic dispersion studies, when the formulation showed accepted release efficiency, no significant precipitation was detected with all the formulation types. In the dissolution studies, all the tested self-emulsifying formulations showed superior dissolution profiles compared with Stugeron® tablets in both simulated gastric fluid (SGF) and simulated alkaline fluid (SIF). Upon shifting from SGF to SIF, Stugeron® showed significant precipitation (leaving only 8-13% CN in solution) while the self-emulsifying formulations were able to hold more than 74% CN in solution. All the formulations investigated in the dissolution studies were also included in the stability assessment studies. The accelerated stability study revealed significant degradation within all the formulations. On the other hand, the long term stability study revealed that formulations containing saturated medium chain glycerides were able to provide good chemical and physical stability up to 6 months. Conclusion: Self-emulsifying formulations represent a valuable option to improve the oral bioavailability of PWSD compounds. However, the selection of components and their relative quantities in the formulation are very critical and vary from drug to another. The optimum formulation selection depends mainly on the physico-chemical properties of each drug. Formulations containing medium chain mixed glycerides showed remarkable suitability for CN. Regardless of the surfactant type, formulations containing medium chain mixed glycerides showed enhanced self-emulsifying efficiency, satisfactory CNsolubility, low droplet size, superior dissolution and better CN-stability profiles. Accordingly, the choice of lipid (oil) seems to be the most vital step in designing the CN self-emulsifying formulations